title: Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia.
abstract: It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR) functions as well as exacerbation of symptoms in response to NMDAR antagonists. Abnormal NMDAR signaling presumably contributes to cognitive deficits which substantially contribute to functional disability in schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms of hypoglutmatergic neurotransmission in schizophrenia. Here, we examined the responses of Sp4 hypomorphic mice to NMDAR antagonists in electroencephalography and various behavioral paradigms. Sp4 hypomorphic mice, previously reported to have reduced NMDAR1 expression and LTP deficit in hippocampal CA1, displayed increased sensitivity and prolonged responses to NMDAR antagonists. Molecular studies demonstrated reduced expression of glutamic acid decarboxylase 67 (GAD67) in both cortex and hippocampus, consistent with abnormal gamma oscillations in Sp4 hypomorphic mice. On the other hand, human SP4 gene was reported to be deleted in schizophrenia. Several human genetic studies suggested the association of SP4 gene with schizophrenia and other psychiatric disorders. Therefore, elucidation of the Sp4 molecular pathway in Sp4 hypomorphic mice may provide novel insights to our understanding of abnormal NMDAR signaling in schizophrenia.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Baohu
authors.initials: B
authors.lastname: Ji
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Antonio
authors.initials: A
authors.lastname: Pinto-Duarte
authors.forename: Minjung
authors.initials: M
authors.lastname: Kim
authors.forename: Sorana
authors.initials: S
authors.lastname: Caldwell
authors.forename: Jared W
authors.initials: JW
authors.lastname: Young
authors.forename: Margarita M
authors.initials: MM
authors.lastname: Behrens
authors.forename: Terrence J
authors.initials: TJ
authors.lastname: Sejnowski
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
authors.forename: Xianjin
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007649:Ketamine / Q000494:pharmacology*; D017774:Long-Term Potentiation; D051379:Mice; D010641:Phenotype; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction; D051706:Sp4 Transcription Factor / Q000235:genetics*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D051706:Sp4 Transcription Factor; C497125:Sp4 protein, mouse; D007649:Ketamine